Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The therapeutic agent for AIDS is mainly selected from a group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g., Indinavir), but they are proved to cause side effects such as nephropathy and the emergence of resistant viruses. Thus, the development of anti-HIV agents having other mechanisms of action has been desired.
A combination therapy is reported to be efficient in the treatment for AIDS because of the frequent emergence of the resistant mutant (Ref: non-patent document 1). Reverse transcriptase inhibitors and protease inhibitors are clinically used as anti-HIV agents, but agents having the same mechanism of action often exhibit cross-resistance or only an additive effect. Therefore, anti-HIV agents having the other mechanism of action have been desired.
Some integrase inhibitors have recently been reported, for Example, 1,3-dioxo butenoic acids or 1,3-propandionse disclosed (patent document 1 to 6).
Also, the integrase inhibitors having a similar structure to the present compound have been known (patent document 7 to 12). In addition, virus inhibitors having a similar structure to the present compound have been known (patent document 13 to 15). Benzimidazole derivatives that are anti-platelet agents having a similar structure to the present compound are disclosed (non-patent document 2).
Further, as a compound having HIV integrase inhibitory activity, a compound of the following formula is disclosed:
wherein Rc is hydroxy or alkoxy, Z2′ is alkylene or alkenylene, R1′ is an optionally substituted aryl or an optionally substituted heteroaryl. (patent document 16, non-patent document 3)
Furthermore, 5-benzyl-7-acetyl-8-hydroxyquinoline and 5-phenyl-7-acetyl-8-hydroxyquinoline are disclosed (patent document 17).
In addition, patent document 18 discloses a method for synthesizing the quinoline nucleus of the present invention. However, said process needs many steps, and the development of a more efficient process has been desired. As a known method for synthesis of quinoline nucleus, Skraup reaction has been known (non-patent document 4).    (non-patent document 1) Balzarini, J. et al, Proc. Natl. Acad. Sci. USA 1996, 93, p13152-13157    (non-patent document 2) Chem. Pharm. Bull. 42(3) 560-569 (1994)    (non-patent document 3) J. Med. Chem. 2000, 43, 1533-1540    (non-patent document 4) Organic Reactions, vol. 7 p. 59 (1953)    (patent document 1) WO99/50245    (patent document 2) WO99/62520    (patent document 3) WO99/62897    (patent document 4) WO99/62513    (patent document 5) WO00/39086    (patent document 6) WO01/00578    (patent document 7) WO2002/30426    (patent document 8) WO2002/30930    (patent document 9) WO2002/30931    (patent document 10) WO2002/36734    (patent document 11) WO2002/55079    (patent document 12) WO02/070486    (patent document 13) WO02/04444    (patent document 14) JP-A-2001-526265 (Tokuhyou)    (patent document 15) JP-A-2002-505660 (Tokuhyou)    (patent document 16) WO98/45269    (patent document 17) U.S. Pat. No. 3,113,135    (patent document 18) WO 02/070486